Case 4 -

Lobular Carcinoma in Situ (LCIS) (E-cadherin Negative) with Comedonecrosis, Present at the Inked Margin Edi Brogi Memorial Sloan-Kettering Cancer Center New York, NY

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Clinical History: A 44 year old woman underwent excision of new mammographic calcifications in the left breast. The diagnosis was "intraductal carcinoma, solid type with comedonecrosis and calcifications, close to the margin". Re-excision yielded the findings shown in Figures 1-5; the findings in figure 6 were not noted. More surgery followed, showing "multifocal LCIS, extending into ducts, with foci of comedonecrosis, present at two distinct foci of the inked resection margin." The patient received no radiotherapy. Ten years later, new pleomorphic calcifications were detected in the same breast, as well as ipsilateral axillary lymphadenopathy. Biopsy showed invasive lobular carcinoma with lymph node metastases. The patient received neo-adjuvant chemotherapy, and later underwent left modified radical mastectomy. A year later she developed cerebellar metastases with leptomeningeal involvement and died of disease. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 Extensive solid carcinoma in situ is present, centered in the TDLU. Some of the acini show massive distention and central necrosis. Case 4 - Figure 2 Extensive solid carcinoma in situ is present, centered in the TDLU. Some of the acini show massive distention and central necrosis. Case 4 - Figure 3 Massively expanded acini with central necrosis abut the inked margin. Case 4 - Figure 4 The carcinoma consists of a monotonous proliferation of small cells, with central nucleus. Few large histiocytes are admixed with the carcinoma in situ. Case 4 - Figure 5 The carcinoma in situ consists of small cells, with scant cytoplasm and inconspicuous nucleoli. Rare binucleate cells are present. Intracytoplasmic vacuoles indent some of the nuclei, with resulting signet ring morphology. Case 4 - Figure 6 Scattered tumor cells admixed with few lymphocytes are present in the stroma adjacent to in situ carcinoma. This focus, not present in the original slides, was unveiled only in a deeper section. Microscopic description The in situ carcinoma in this case consists of a solid and monotonous proliferation of small and slightly dishesive cells expanding lobules and small ducts. Few acini show massive distension (more than 100 cells across), with focal central necrosis and associated calcifications. No gland formation and no polarized cells are present. The nuclei are small to slightly enlarged (1.5-2X RBC), have central or slightly eccentric position within the cell and show low grade atypia. The neoplastic cells are morphologically consistent with type A (small) and type B (large) classic LCIS cells, however, the presence of focal necrosis with associated calcifications is unusual in a lobular lesion, and suggests DCIS. A focus of microinvasive lobular carcinoma (not present in the original slides) is identified in a deeper section obtained from one of the tissue blocks. Few ducts involved by CIS with central necrosis are close to or transected at the margin. Classic LCIS is also present, merging with the solid carcinoma. The neoplastic cells showed no membranous immunoreactivity for E-cadherin (not shown). Differential diagnosis The differential diagnosis in this case is between low grade DCIS versus an unusual variant of LCIS. The diagnostic dilemma is also reflected in the original diagnoses rendered for this neoplasm, which ranged from "intraductal carcinoma, solid type, with comedonecrosis" to "LCIS with comedonecrosis". This case prompts a discussion about: use of E-cadherin immunostain as an aid in the differential diagnosis of solid mammary carcinoma in situ (CIS); biology and management of E-cadherin negative CIS with morphologic features intermediate between DCIS and LCIS. E-cadherin and classification of mammary solid carcinoma in situ E-cadherin is a transmembrane glycoprotein involved in cell-to-cell adhesion through Ca2+-dependent homotypic binding. The encoding gene (CDH1) maps to chromosome 16q22.1. The normal mammary epithelium expresses E-cadherin and displays strong, linear and continuous membranous immunoreactivity for this antigen. The same staining pattern is observed in ductal carcinomas. The myoepithelium also expresses E-cadherin, but shows granular and discontinuous ("dot-like") membranous reactivity. In contrast, the E-cadherin gene is consistently lost and/or functionally inactivated in lobular neoplasia, resulting in loss of membranous positivity in all lobular lesions. Therefore, immunoperoxidase staining for E-cadherin is widely used at most centers to confirm lobular differentiation. The widespread application of this staining has revealed that some solid CIS with ambiguous morphology are E-cadherin negative, consistent with lobular differentiation. In the discussion of this case, we will focus our attention on E-cadherin negative carcinomas in situ with morphology different from that of classic LCIS, with some comments regarding biology and management of these tumors, and then briefly review some aberrant patterns of E-cadherin immunostain. E-Cadherin negative CIS = Special variants of LCIS a) Morphology E-cadherin negative CIS with ambiguous morphology are usually characterized by massive expansion of ducts and lobules by dishesive neoplastic cells showing central necrosis and associated calcifications. They can roughly be divided into two subgroups depending on cell morphology: A) E-cadherin negative solid mammary CIS composed of type A (small) and/or type B (large) LCIS cells with comedo-type necrosis (like the current case). Jacobs described 6 tumors with this morphology [1] and Maluf reported 3 [2]. Fadare and colleagues reported 18 cases, the largest series to date, which they called "LCIS with comedonecrosis" [3]. Rosen refers to these lesions as "florid LCIS with necrosis" [4]. Despite the typical type A and/or type B LCIS cytomorphology, these tumors differ from classic LCIS because of central necrosis and massive acinar expansion (more than 100 cells across) (Table I). B) E-cadherin negative solid mammary CIS composed of large and dishesive pleomorphic cells. The neoplastic cells show abundant cytoplasm and plasmacytoid morphology. Marked nuclear enlargement (>3X size of a lymphocyte) and nuclear membrane irregularities are present, with prominent nucleoli. The nuclear atypia is similar to that of intermediate nuclear grade ductal carcinoma. Central necrosis and associated calcifications are usually present. Jacobs described 5 tumors with this morphology [1], but the term "pleomorphic" LCIS was first introduced by Sneige [5]. The cells of pleomorphic LCIS do not resemble those of classic LCIS, but the finding of marked dishesion, a morphologic correlate of E-cadherin negativity, is a useful clue to the diagnosis (Table I) . In situ (and invasive) pleomorphic lobular carcinoma has a pattern of E-cadherin inactivation [6] and bears genetic alterations [7, 8] consistent with lobular differentiation. At present, it is generally accepted that E-cadherin negative CIS represent special variants of LCIS [9] , but no real uniform consensus exists on these lesions. Special LCIS are usually ER and PR positive, Her-2 negative [3, 5], although positivity for Her-2 has been reported [10]. Lobular neoplasia also shows cytoplasmic positivity for p120 [11, 12] , the cytoplasmic ligand of E-cadherin, and for keratin 34 b E12 [13, 14] , but no specific information is available about the expression of these markers in special LCIS. b) Biology and treatment Information on the biology of special LCIS is extremely limited, as in the past they were diagnosed and treated as DCIS. Whereas classic LCIS is an incidental histologic finding, Sapino and colleagues have reported 10 cases of special LCIS which were detected mammographically because of associated calcifications. The calcifications were limited to one quadrant in 7 cases, and present throughout the entire breast in 3. Invasive carcinoma was identified in four of the ten cases. Seven patients underwent mastectomy, and the remaining 3 were treated with breast conservation, and showed no evidence of disease at the time of the study, but follow-up was short (range 2-11 months) [10]. Of note, there is uniform consensus that any lesion yielding special LCIS in a core biopsy needs to be excised. All patients with "LCIS with comedonecrosis" reported by Fadare and colleagues were women, ranging in age from 41 to 85 years (mean 61.3). Twelve lesions were identified in breast excisions or mastectomy specimens and 6 in incisional biopsies. Six patients had only in situ carcinoma (33%). The invasive carcinoma in the remaining 12 cases (67%) was predominantly lobular (7 classic lobular, 1 pleomorphic lobular, 1 ductal, 1 mixed ductal and lobular, 1 tubular and one case with separate ductal and lobular carcinomas). Calcifications were associated with the tumor in 10/18 cases (55%). On core biopsy material, two cases were initially diagnosed as DCIS and the patients received radiation; one of the two recurred seven years later with LCIS with comedonecrosis without invasion. No additional follow-up was available for any of the other cases [3]. Sneige and colleagues studied 24 cases of pleomorphic LCIS, including 10 in situ (42%), and 14 with associated invasive pleomorphic lobular carcinoma. Classic LCIS with type A and type B morphology coexisted with pleomorphic LCIS in 40% of these cases and transition into pleomorphic LCIS was observed in four. Of the 10 patients with only pleomorphic LCIS, 5 were managed conservatively, and two underwent mastectomy. Six of these patients had no evidence of disease in follow-up periods ranging from 4 to 32 months, whereas the seventh recurred after 12 months with carcinoma in situ morphologically similar to the prior [5]. This data document that special variants of LCIS are very rare and seldom occur in isolation (only about 40% of reported cases). The frequent association with invasive carcinoma, which is usually of lobular type, suggests a more aggressive behavior than classic LCIS. In the current case microinvasive lobular carcinoma was present, admixed with focal chronic inflammation. The case discussed here was initially diagnosed as DCIS with necrosis, but the patient did not receive radiation therapy. "LCIS with comedonecrosis" was present at the margin of her final re-excision specimen, but no additional surgery was performed, as for classic LCIS. Regarding margin status, the latest WHO book recommendations state that "re-excision should be considered in cases with massive acinar distention, and when pleomorphic, signet ring or necrotic variants are identified at or close to the margin" [9]. Classic LCIS is usually found near special LCIS variants, as it was in this case. This patient recurred with invasive lobular carcinoma about 10 years after the initial diagnosis and died of disease shortly after. This case highlights the aggressive biology of LCIS with comedonecrosis, a special type of LCIS. Diagnosis Lobular carcinoma in situ (LCIS) (E-cadherin negative) with comedonecrosis, present at the inked margin. Focal microinvasive lobular carcinoma. Unusual or aberrant E-cadherin staining patterns Although E-cadherin is a reliable tool in the differential between ductal and lobular carcinoma, aberrant and/or mixed patterns of immunoreactivity have been reported. Jacobs described 6 cases of CIS with indeterminate features which showed a mixed pattern of E-cadherin positivity, suggesting a mixed DCIS/LCIS phenotype [1]. Maluf had 2 of such cases [2] and Goldstein reported 17 more [15]. From a practical standpoint, finding of any E-cadherin positivity is usually regarded as supportive evidence of ductal differentiation. Recently, however, Da Silva and colleagues have reported aberrant positivity for E-cadherin in LCIS [16] . This unusual finding can possibly lead to overdiagnose of DCIS, especially in the assessment of margin status [16]. Aberrant expression of E-cadherin, including positive staining in areas with lobular morphology and negative staining in areas with obvious gland formation, has also been described in 5 cases of invasive carcinoma [17]. Mahler-Araujo and colleagues have observed reduction or complete loss of E-cadherin immunoreactivity in some non-lobular breast carcinomas. E-cadherin staining was negative in 34.6% of triple negative carcinomas, and in 40.7% of basal carcinomas (defined as triple negative and either EGFR and/or CK5/6 positive). Interestingly, the group of E-cadherin negative carcinomas also included 11.3% of ER positive tumors, and 21.1% of grade 1 tumors (4 cases only), in addition to grade 3 carcinomas (17.4%) [18]. We have also observed sporadic cases of aberrant reactivity for E-cadherin, most often characterized by loss of membranous reactivity in lesions with obvious ductal morphology. Therefore, caution should always be used in the analysis of E-cadherin immunoreactivity (just as for any other immunostaining pattern), and the results should always be interpreted in combination with morphology. Take home points E-cadherin immunoreactivity is useful in the diagnostic evaluation of carcinomas in situ with indeterminate features. Lack of membranous immunoreactivity for E-cadherin supports lobular differentiation in most cases, but few exceptions exist. The differential diagnosis of solid carcinoma in situ with necrosis and calcifications includes special variants of LCIS. Special LCIS variants are more aggressive than classic LCIS. Additional surgery is recommended when special LCIS with central necrosis and massive acinar distention is present at or near a margin. Table I - Morphologic Features Helpful in the Differential Diagnosis of Classic LCIS Versus Special LCIS Versus DCIS C-LCIS S-LCIS DCIS Dishesive Growth Present Present Absent Cell Polarity Absent Absent Usually Present Tdlu Involvement Typical, Distended Acini Typical, Massive Acinar Expansion Possible "Lobular Cancerization" Interdigitating Myoepithelium Common May be Focally Present Absent Necrosis Absent Often Present Often Present Mitoses Absent Present Present Calcifications Rare Frequent Frequent Cell Shape Round "Fried Egg" Round to Plasmacytoid Columnar Cytoplasm Scant Scant to Abundant Variable Nuclear Pleomorphism Absent Present in Pleomorphic Variant Absent to Present Nucleoli Rare Common Common Associated Invasive Carcinoma Possible Frequent Possible to Frequent C-LCIS= classical LCIS; S-LCIS= special variants of LCIS Reference: Jacobs TW, Pliss N, Kouria G, Schnitt SJ. 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